Combination IFNß and Membrane-Stable CD40L Maximize Tumor Dendritic Cell Activation and Lymph Node Trafficking to Elicit Systemic T-cell Immunity.
Cancer Immunol Res
; 11(4): 466-485, 2023 04 03.
Article
em En
| MEDLINE
| ID: mdl-36757308
ABSTRACT
Oncolytic virus therapies induce the direct killing of tumor cells and activation of conventional dendritic cells (cDC); however, cDC activation has not been optimized with current therapies. We evaluated the adenoviral delivery of engineered membrane-stable CD40L (MEM40) and IFNß to locally activate cDCs in mouse tumor models. Combined tumor MEM40 and IFNß expression induced the highest cDC activation coupled with increased lymph node migration, increased systemic antitumor CD8+ T-cell responses, and regression of established tumors in a cDC1-dependent manner. MEM40 + IFNß combined with checkpoint inhibitors led to effective control of distant tumors and lung metastases. An oncolytic adenovirus (MEM-288) expressing MEM40 + IFNß in phase I clinical testing induced cancer cell loss concomitant with enhanced T-cell infiltration and increased systemic presence of tumor T-cell clonotypes in non-small cell lung cancer (NSCLC) patients. This approach to simultaneously target two major DC-activating pathways has the potential to significantly affect the solid tumor immunotherapy landscape.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Pulmonar de Células não Pequenas
/
Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cancer Immunol Res
Ano de publicação:
2023
Tipo de documento:
Article